Publications by authors named "Abedawn I Khalaf"

30 Publications

  • Page 1 of 1

Selective anti-cancer activity of non-alkylating minor groove binders.

Medchemcomm 2019 Sep 18;10(9):1620-1634. Epub 2019 Jul 18.

Department of Pure and Applied Chemistry , WestCHEM , University of Strathclyde , Glasgow , UK . Email:

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.
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http://dx.doi.org/10.1039/c9md00268eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478159PMC
September 2019

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model.

J Med Chem 2019 03 13;62(6):3021-3035. Epub 2019 Mar 13.

Department of Biological and Geographical Sciences, School of Applied Sciences , University of Huddersfield , Huddersfield HD1 3DH , U.K.

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01847DOI Listing
March 2019

Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis.

Acta Trop 2018 Sep 23;185:212-218. Epub 2018 May 23.

Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow, G4 0RE, UK. Electronic address:

Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested - 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.
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http://dx.doi.org/10.1016/j.actatropica.2018.05.015DOI Listing
September 2018

Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy.

J Antimicrob Chemother 2017 Dec;72(12):3334-3341

University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.

Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb.

Methods: The mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation.

Results: H37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 μM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation.

Conclusions: MGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.
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http://dx.doi.org/10.1093/jac/dkx326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890746PMC
December 2017

An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics.

Eur J Med Chem 2017 Aug 17;136:561-572. Epub 2017 May 17.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MICs of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans.MGB-353 and MGB-354 have MICs of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.039DOI Listing
August 2017

Four pyrrole derivatives used as building blocks in the synthesis of minor-groove binders.

Acta Crystallogr E Crystallogr Commun 2017 Feb 27;73(Pt 2):254-259. Epub 2017 Jan 27.

Westchem, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland.

The title nitro-pyrrole-based compounds, CHNO, (I) (ethyl 4-nitro-1-pyrrole-2-carboxyl-ate), its derivative CHNO, (II) [ethyl 4-nitro-1-(4-pent-yn-yl)-1-pyrrole-2-carboxyl-ate], CHNO, (III) {-[3-(di-methyamino)prop-yl]-1-isopentyl-4-nitro-1-pyrrole-2-carboxamide}, and CHNO, (IV) {1-(3-azido-prop-yl)-4-(1-methyl-4-nitro-1-pyrrole-2-carboxamido)--[2-(morpholin-4-yl)eth-yl]-1-pyrrole-2-carboxamide}, are inter-mediates used in the synthesis of modified DNA minor-groove binders. In all four compounds, the nitro groups lie in the plane of the pyrrole ring. In compounds (I) and (II), the ester groups also lie in the plane of the pyrrole ring. In compound (III), both of the other substituents lie out of the plane of the pyrrole ring. In the case of compound (IV), the coplanarity extends to the second pyrrole ring and through both amide groups. In the crystals of all four compounds, layer-like structures are formed, a combination of N-H⋯O and C-H⋯O hydrogen bonds for (I), (III) and (IV), but by only C-H⋯O hydrogen bonds for (II).
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http://dx.doi.org/10.1107/S2056989017001177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290577PMC
February 2017

An evaluation of Minor Groove Binders as anti-lung cancer therapeutics.

Bioorg Med Chem Lett 2016 08 16;26(15):3478-86. Epub 2016 Jun 16.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cancer.
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http://dx.doi.org/10.1016/j.bmcl.2016.06.040DOI Listing
August 2016

Selective anti-malarial minor groove binders.

Bioorg Med Chem Lett 2016 07 13;26(14):3326-3329. Epub 2016 May 13.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.039DOI Listing
July 2016

An evaluation of Minor Groove Binders as anti-Trypanosoma brucei brucei therapeutics.

Eur J Med Chem 2016 Jun 29;116:116-125. Epub 2016 Mar 29.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activity.
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http://dx.doi.org/10.1016/j.ejmech.2016.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872591PMC
June 2016

Crystal structure of N,N-dimethyl-2-[(4-methyl-benz-yl)sulfon-yl]ethanamine.

Acta Crystallogr E Crystallogr Commun 2015 Jul 6;71(Pt 7):757-9. Epub 2015 Jun 6.

Westchem, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland.

In the crystal, the title compound, C12H19NO2S, has a disordered structure with two equally populated conformations of the amine fragment. A pair of weak C-H⋯O inter-molecular inter-actions between the CH2 and SO2 groups gives a one-dimensional supra-molecular structure that propagates through translation along the a-axis direction.
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http://dx.doi.org/10.1107/S2056989015010233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518984PMC
July 2015

Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome.

J Autoimmun 2015 Jun 11;60:59-73. Epub 2015 May 11.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address:

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2(-/-) mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.
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http://dx.doi.org/10.1016/j.jaut.2015.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459730PMC
June 2015

Recognition of the DNA minor groove by thiazotropsin analogues.

Chembiochem 2014 Sep 16;15(13):1978-90. Epub 2014 Jul 16.

Department of Pharmacy, An-Najah National University, University Street, Nablus (Palestine); Present address: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2J7 (Canada).

Solution-phase self-association characteristics and DNA molecular-recognition properties are reported for three close analogues of minor-groove-binding ligands from the thiazotropsin class of lexitropsin molecules; they incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPy(iPr) ThDp) shows similar self-assembly characteristics to thiazotropsin A (FoPyPy(iPr) ThDp), although it is engineered, by incorporation of imidazole in place of N-methyl pyrrole, to swap its DNA recognition target from 5'-ACTAGT-3' to 5'-ACGCGT-3'. Replacement of the formamide head group in thiazotropsin A by nicotinamide in AIK-18/51 results in a measureable difference in solution-phase self-assembly character and substantially enhanced DNA association characteristics. The structures and associated thermodynamic parameters of self-assembled ligand aggregates and their complexes with their respective DNA targets are considered in the context of cluster targeting of DNA by minor-groove complexes.
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http://dx.doi.org/10.1002/cbic.201402202DOI Listing
September 2014

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.

J Med Chem 2014 Aug 29;57(15):6479-94. Epub 2014 Jul 29.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.
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http://dx.doi.org/10.1021/jm500483bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136963PMC
August 2014

Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties.

Int J Parasitol 2014 Aug 12;44(9):669-74. Epub 2014 Jun 12.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK. Electronic address:

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflammatory properties by virtue of covalently attached phosphorylcholine moieties. Screening of a library of ES-62 phosphorylcholine-based small molecule analogues (SMAs) revealed that two compounds, termed 11a and 12b, mirrored the helminth product both in inhibiting mast cell degranulation and cytokine responses in vitro and in preventing ovalbumin-induced Th2-associated airway inflammation and eosinophil infiltration of the lungs in mice. Furthermore, the two SMAs inhibited neutrophil infiltration of the lungs when administered therapeutically. ES-62-SMAs 11a and 12b thus represent starting points for novel drug development for allergies such as asthma.
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http://dx.doi.org/10.1016/j.ijpara.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119935PMC
August 2014

Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

J Med Chem 2013 Dec 25;56(24):9982-10002. Epub 2013 Nov 25.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0RE, U.K.

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.
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http://dx.doi.org/10.1021/jm401251pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125414PMC
December 2013

Thiazotropsin aggregation and its relationship to molecular recognition in the DNA minor groove.

Biophys Chem 2013 Sep 25;179:1-11. Epub 2013 Apr 25.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

Aggregated states have been alluded to for many DNA minor groove binders but details of the molecule-on-molecule relationship have either been under-reported or ignored. Here we report our findings from ITC and NMR measurements carried out with AIK-18/51, a compound representative of the thiazotropsin class of DNA minor groove binders. The free aqueous form of AIK-18/51 is compared with that found in its complex with cognate DNA duplex d(CGACTAGTCG)2. Molecular self-association of AIK-18/51 is consistent with anti-parallel, face-to-face dimer formation, the building block on which the molecule aggregates. This underlying structure is closely allied to the form found in the ligand's DNA complex. NMR chemical shift and diffusion measurements yield a self-association constant Kass=(61±19)×10(3)M(-1) for AIK-18/51 that fits with a stepwise self-assembly model and is consistent with ITC data. The deconstructed energetics of this assembly process are reported with respect to a design strategy for ligand/DNA recognition.
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http://dx.doi.org/10.1016/j.bpc.2013.04.001DOI Listing
September 2013

Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups.

Eur J Med Chem 2012 Oct 16;56:39-47. Epub 2012 Aug 16.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.

The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.
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http://dx.doi.org/10.1016/j.ejmech.2012.08.013DOI Listing
October 2012

Amide isosteres in structure-activity studies of antibacterial minor groove binders.

Eur J Med Chem 2011 Nov 30;46(11):5343-55. Epub 2011 Aug 30.

WestCHEM Research School, Department of Pure & Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.

Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis.
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http://dx.doi.org/10.1016/j.ejmech.2011.08.035DOI Listing
November 2011

Ranking ligand affinity for the DNA minor groove by experiment and simulation.

ACS Med Chem Lett 2010 Nov 30;1(8):376-80. Epub 2010 Jul 30.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom.

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor groove binders (MGBs) with DNA is not fully understood. In 2003, we reported the first example of a thiazole-containing MGB that bound in a phase-shifted pattern that spanned six base pairs rather than the usual four (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, NMR spectroscopy, isothermal titration calorimetry, and molecular dynamics, we have established that the flanking bases around the central four being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences.
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http://dx.doi.org/10.1021/ml100047nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007966PMC
November 2010

A detailed binding free energy study of 2:1 ligand-DNA complex formation by experiment and simulation.

Phys Chem Chem Phys 2009 Dec 22;11(45):10682-93. Epub 2009 Sep 22.

Chemistry Department and Center of Nanotechnology, Kasetsart University, Bangkok 10900, Thailand.

In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2:1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol(-1)) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol(-1)). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development.
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http://dx.doi.org/10.1039/b910574cDOI Listing
December 2009

A new synthesis of alkene-containing minor-groove binders and essential hydrogen bonding in binding to DNA and in antibacterial activity.

Org Biomol Chem 2009 May 12;7(9):1843-50. Epub 2009 Mar 12.

Strathclyde Institute of Pharmacy and Biomedical Sciences, The John Arbuthnott Building, 27 Taylor Street, Glasgow, G4 0NR, Scotland.

A practical synthesis of alkene-containing minor-groove binders for DNA, related to distamycin, with potential for wide structural diversity is described, based upon the Wittig chemistry of N-alkylpyrrole aldehydes. The compounds prepared have been evaluated for binding to DNA by physical methods (melting temperature and NMR) and for their antibacterial activity. Significantly, it was found that alkenes linking the aryl head group of the minor-groove binder promote strong binding to DNA and high antibacterial activity against Gram-positive bacteria. Conversely, a minor-groove binder containing an alkene located towards the alkylamino tail group has a low affinity for DNA and does not show antibacterial activity. These observations suggest an important role for specific hydrogen bonds in the binding of compounds of this type to DNA, and in their antibacterial activity.
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http://dx.doi.org/10.1039/b901898kDOI Listing
May 2009

2,2,2-Trifluoro-N-(isoquinolin-5-ylmeth-yl)acetamide.

Acta Crystallogr Sect E Struct Rep Online 2009 Dec 12;66(Pt 1):o135. Epub 2009 Dec 12.

Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland.

The mol-ecular structure of the title compound at 123 K, C(12)H(9)F(3)N(2)O, presents a rotationally disordered CF(3) group. Hydrogen bonds between the amide NH group and the N atom of the isoquinoline form a chain in the b-axis direction. The packed structure forms alternate layers of isoquinoline and amide groups parallel to the ab plane.
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http://dx.doi.org/10.1107/S1600536809052994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980156PMC
December 2009

Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups.

J Med Chem 2007 Nov 26;50(24):6116-25. Epub 2007 Oct 26.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, U.K.

The synthesis and properties of 80 short minor groove binders related to distamycin and the thiazotropsins are described. The design of the compounds was principally predicated upon increased affinity arising from hydrophobic interactions between minor groove binders and DNA. The introduction of hydrophobic aromatic head groups, including quinolyl and benzoyl derivatives, and of alkenes as linkers led to several strongly active antibacterial compounds with MIC for Staphylococcus aureus, both methicillin-sensitive and -resistant strains, in the range of 0.1-5 microg mL-1, which is comparable to many established antibacterial agents. Antifungal activity was also found in the range of 20-50 microg mL-1 MIC against Aspergillus niger and Candida albicans, again comparable with established antifungal drugs. A quinoline derivative was found to protect mice against S. aureus infection for a period of up to six days after a single intraperitoneal dose of 40 mg kg-1.
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http://dx.doi.org/10.1021/jm070831gDOI Listing
November 2007

M4 agonists/5HT7 antagonists with potential as antischizophrenic drugs: serominic compounds.

Bioorg Med Chem Lett 2007 May 2;17(9):2649-55. Epub 2007 Feb 2.

Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, UK.

Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT(7) antagonists and M(4) agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.093DOI Listing
May 2007

DNA sequence recognition by an imidazole-containing isopropyl-substituted thiazole polyamide (thiazotropsin B).

Bioorg Med Chem Lett 2006 Jul 27;16(13):3469-74. Epub 2006 Apr 27.

School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.

We have used DNA footprinting and fluorescence melting experiments to study the sequence specific binding of an imidazole-containing isopropyl-substituted thiazole polyamide (thiazotropsin B) to DNA. While the parent compound (thiazotropsin A) binds to the hexanucleotide sequence ACTAGT, changing one of the N-methylpyrrole groups to N-methylimidazole changes the preferred binding sequence to (A/T)CGCG(T/A). Experiments with DNA fragments that contain variants of this sequence suggest that the ligand can also bind, with lower affinity, to sequences which differ from this by 1bp in any position.
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http://dx.doi.org/10.1016/j.bmcl.2006.04.007DOI Listing
July 2006

Synthesis and antimicrobial activity of some netropsin analogues.

Org Biomol Chem 2004 Nov 6;2(21):3119-27. Epub 2004 Oct 6.

Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, Scotland, UKG1 1XL.

Nine novel lexitropsins were synthesized by linking two netropsin-like moieties through three different dicarboxylic acids; 9,10-dihydro-2,7-phenanthrenedicarboxylic acid; [(3-[[(carboxymethyl)amino]carbonyl]benzoyl)amino]acetic acid and indole-2,5-dicarboxylic acid. The netropsin residues were modified by the use of N-isopentylpyrrole, 5-methylthiophene or 5-isopropylthiazole heterocyclic building blocks in place of the usual N-methylpyrrole. The compounds were tested against five gram-positive bacteria: Staphylococcus aureus, Streptomyces faecalis, methicillin resistant Staphylococcus aureus, Enterobacter cloacae, Mycobacterium fortuitum, three gram-negative bacteria: Klebsiella aerogenes, Proteus vulgaris, Escherichia coli and three fungi: Aspergillus niger, Candida albicans and Aspergillus nidulans. Some of the compounds showed significant inhibitory effects on the growth of the microorganisms.
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http://dx.doi.org/10.1039/B408386PDOI Listing
November 2004

Short lexitropsin that recognizes the DNA minor groove at 5'-ACTAGT-3': understanding the role of isopropyl-thiazole.

J Am Chem Soc 2004 Sep;126(36):11338-49

Department of Pure and Applied Chemistry, 295 Cathedral Street, Glasgow G1 1XL, UK.

Isopropyl-thiazole ((iPr)Th) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)(2) is bound by a short lexitropsin of sequence formyl-PyPy(iPr)Th-Dp (where Py represents N-methyl pyrrole, (iPr)Th represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT(5)AG(7)T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the (iPr)Th group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G(7) and the (iPr)Th nitrogen, which lies on the minor groove floor. The B(I)/B(II) DNA backbone equilibrium is altered at the T(5) 3'-phosphate position to accommodate a B(II) configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.
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http://dx.doi.org/10.1021/ja030658nDOI Listing
September 2004

DNA sequence recognition by an isopropyl substituted thiazole polyamide.

Nucleic Acids Res 2004 24;32(11):3410-7. Epub 2004 Jun 24.

School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.

We have used DNA footprinting and fluorescence melting experiments to study the sequence-specific binding of a novel minor groove binding ligand (thiazotropsin A), containing an isopropyl substituted thiazole polyamide, to DNA. In one fragment, which contains every tetranucleotide sequence, sub-micromolar concentrations of the ligand generate a single footprint at the sequence ACTAGT. This sequence preference is confirmed in melting experiments with fluorescently labelled oligonucleotides. Experiments with DNA fragments that contain variants of this sequence suggest that the ligand also binds, with slightly lower affinity, to sequences of the type XCYRGZ, where X is any base except C, and Z is any base except G.
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http://dx.doi.org/10.1093/nar/gkh666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC443542PMC
July 2004

Distamycin analogues with enhanced lipophilicity: synthesis and antimicrobial activity.

J Med Chem 2004 Apr;47(8):2133-56

Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, U.K.

Forty-eight heterocyclic amino acid trimers, analogues of distamycin, with a number of features that enhance lipophilicity are described. They contain alkyl or cycloalkyl groups larger than methyl; some are N-terminated by acetamide or methoxybenzamide and are C-terminated by dimethylaminopropyl or aliphatic heterocylic aminopropyl substituents. The ability of these compounds to bind principally to AT tracts of DNA has been evaluated using capillary zone electrophoresis. Significant antimicrobial activity against key organisms such as MRSA and Candida albicans is shown by several compounds, especially those containing a thiazole. Moreover, these compounds have low toxicity with respect to several mammalian cell lines.
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http://dx.doi.org/10.1021/jm031089xDOI Listing
April 2004

DNA binding of a short lexitropsin.

Bioorg Med Chem Lett 2004 Mar;14(5):1353-6

Department of Physiology and Pharmacology, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO9 3TU, UK.

Footprinting, capillary electrophoresis, molecular modelling and NMR studies have been used to examine the binding of a short polyamide to DNA. This molecule, which contains an isopropyl-substituted thiazole in place of one of the N-methylpyrroles, is selective for the sequence 5'-ACTAGT-3' to which it binds with high affinity. Two molecules bind side-by-side in the minor groove, but their binding is staggered so that the molecule reads six base pairs, unlike the related natural products, which tend to bind to four-base-pair sequences. The result suggests that high affinity and selectivity may be gained without resort to very large molecules, which may be difficult to deliver to the site of action.
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http://dx.doi.org/10.1016/j.bmcl.2003.11.068DOI Listing
March 2004